Emodin Regulates Apoptotic Pathway in Human Liver Cancer Cells

Emodin, a natural anthraquinone, has been reported to possess antiproliferative effects in many cancer cell lines. However, anticancer mechanism against human liver cancer remains unclear. In this study, we observed that emodin induced apoptosis in HepG2 cells and caused a significant accumulation of cells in the G1 phase. Western blot data showed that emodin treatment caused the increasing of release of cytochrome c into cytosol from mitochondria and the activation of caspase‐8 and caspase‐9, which suggest that the intrinsic and extrinsic pathways could be involved. Emodin treatment also resulted in a dose‐dependent accumulation of intracellular reactive oxygen species. Furthermore, emodin increased the protein level of p53 and decreased the protein level of NF‐κB/p65 in HepG2 cells, which indicated these two regulators might play a role in emodin‐induced apoptosis. Computational modeling showed that emodin could directly bind to the BH3 domain of Bcl‐2 through forming one hydrogen bond with Ala146 residue in Bcl‐2. From these examinations, emodin not only significantly downregulated expression of Bcl‐2 but also inhibited the heterodimerization of Bcl‐2 with Bax because of strong interaction between emodin and Bcl‐2. These suggest that emodin induces apoptosis in liver cancer cell line through a multifaceted complex cascade of events. Copyright © 2012 John Wiley & Sons, Ltd.     

Growth inhibition and cell cycle arrest in the G0/G1 by schizandrin,a dibenzocyclooctadiene lignan isolated from Schisandra chinensis,on T47D human breast cancer cells

Schizandrin is one of the main dibenzocyclooctadiene lignans present in the fruit of Schisandra chinensis (Schisandraceae). Biological activities including hepatoprotective, antiviral and neuroprotective effects of schizandrin and other dibenzocyclooctadiene lignans have been reported previously. However, the antiproliferative effect of schizandrin against human cancer cells has been poorly determined to date. This study examined the antiproliferative effect of schizandrin in human breast cancer cells. Schizandrin exhibited growth inhibitory activities in cultured human breast cancer cells, and the effect was the more profound in estrogen receptor (ER)‐positive T47D cells than in ER‐negative MDA‐MB‐231 cells. When treated with the compound in T47D cells, schizandrin induced the accumulation of a cell population in the G0/G1 phase, which was further demonstrated by the induction of CDK inhibitors p21 and p27 and the inhibition of the expression of cell cycle checkpoint proteins including cyclin D1, cyclin A, CDK2 and CDK4. These results suggest that schizandrin inhibits cell proliferation through the induction of cell cycle arrest with modulating cell cycle‐related proteins in human breast cancer cells. Copyright © 2009 John Wiley & Sons, Ltd.     

Ramalin‐Mediated Apoptosis Is Enhanced by Autophagy Inhibition in Human Breast Cancer Cells

Breast cancer, the most commonly diagnosed cancer in women worldwide, is treated in various ways. Ramalin is a chemical compound derived from the Antarctic lichen Ramalina terebrata and is known to exhibit antioxidant and antiinflammatory activities. However, its effect on breast cancer cells remains unknown. We examined the ability of ramalin to induce apoptosis and its mechanisms in MCF‐7 and MDA‐MB‐231 human breast cancer cell lines. Ramalin inhibited cell growth and induced apoptosis in both cell lines in a concentration‐dependent manner. By upregulating Bax and downregulating Bcl‐2, ramalin caused cytochrome c and apoptosis‐inducing factor to be released from the mitochondria into the cytosol, thus activating the mitochondrial apoptotic pathway. In addition, activated caspase‐8 and caspase‐9 were detected in both types of cells exposed to ramalin, whereas ramalin activated caspase‐3 only in the MDA‐MB‐231 cells. Ramalin treatment also increased the levels of LC3‐II and p62. Moreover, the inhibition of autophagy by 3‐methyladenine or Atg5 siRNA significantly enhanced ramalin‐induced apoptosis, which was accompanied by a decrease in Bcl‐2 levels and an increase in Bax levels. Therefore, autophagy appears to be activated as a protective mechanism against apoptosis in cancer cells exposed to ramalin. These findings suggest that ramalin is a potential anticancer agent for the treatment of patients with non‐invasive or invasive breast cancer. Copyright © 2015 John Wiley & Sons, Ltd.     

Fangchinoline Induces G1 Arrest in Breast Cancer Cells Through Cell‐Cycle Regulation

Fangchinoline, an alkaloid derived from the dry roots of Stephaniae tetrandrine S. Moore (Menispermaceae), has been shown to possess cytotoxic, anti‐inflammatory, and antioxidant properties. In this study, we used Fangchinoline to inhibit breast cancer cell proliferation and to investigate its underlying molecular mechanisms. Human breast cancer cell lines, MCF‐7 and MDA‐MB‐231, were both used in this study. We found that Fangchinoline significantly decreased cell proliferation in a dose‐dependent manner and induced G1‐phase arrest in both cell lines. In addition, upon analysis of expression of cell cycle‐related proteins, we found that Fangchinoline reduced expression of cyclin D1, cyclin D3, and cyclin E, and increased expression of the cyclin‐dependent kinase (CDK) inhibitors, p21/WAF1, and p27/KIP1. Moreover, Fangchinoline also inhibited the kinase activities of CDK2, CDK4, and CDK6. These results suggest that Fangchinoline can inhibit human breast cancer cell proliferation and thus may have potential applications in cancer therapy. Copyright © 2013 John Wiley & Sons, Ltd.     

α‐Hederin induces the apoptosis of gastric cancer cells accompanied by glutathione decrement and reactive oxygen species generation via activating mitochondrial dependent pathway

α‐Hederin, a monodesmosidic triterpenoid saponin, exhibited promising antitumor potential against a variety of human cancer cell lines. However, few related studies about effects of α‐hederin on gastric cancer are available. Herein, our results showed that α‐hederin significantly inhibited the proliferation of gastric cancer cells and arrested the cell cycle in G1 phase in vitro (p < .05). Further research of the potential mechanism reflected that α‐hederin could induce intracellular glutathione decrement, adenosine triphosphate level, and mitochondrial membrane potential variation via inducing reactive oxygen species accumulation during the apoptosis of gastric cancer cells. Moreover, the detection of mitochondrial and cytosol proteins with apoptosis‐inducing factor, apoptosis protease activating factor‐1, and cytochrome C showed an increase in the cytosol, followed by a decrease of Bcl‐2 levels and increases of caspase‐3, caspase‐8, caspase‐9, and Bax, which revealed that α‐hederin induced apoptosis via triggering activation of the mitochondrial pathway. Furthermore, the above changes were amplified when pretreated with buthionine sulfoximine, whereas attenuated in the group pretreated with NAC than α‐hederin alone (p < .05). In addition, α‐hederin significantly inhibited the growth of xenografted gastric tumors with favorable safety. In conclusion, α‐hederin could inhibit the proliferation and induce apoptosis of gastric cancer accompanied by glutathione decrement and reactive oxygen species generation via activating mitochondrial dependent pathway.     

3,4,5‐Tricaffeoylquinic Acid Attenuates TRAIL‐induced Apoptosis in Human Keratinocytes by Suppressing Apoptosis‐related Protein Activation

Caffeoyl derivatives exhibit antiinflammatory and antioxidant effects. However, the effect of 3,4,5‐tricaffeoylquinic acid on the tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced apoptosis in keratinocytes that may be involved in skin diseases has not been studied. In this respect, we investigated the effect of 3,4,5‐tricaffeoylquinic acid on TRAIL‐induced apoptosis in human keratinocytes. 3,4,5‐Tricaffeoylquinic acid and oxidant scavengers attenuated the decrease in the cytosolic levels of Bid, Bcl‐2, and survivin proteins; the increase in the levels of cytosolic Bax, p53, and phosphorylated p53; the increase in the levels of phosphorylated p38; the increase in the mitochondrial levels of the voltage‐dependent anion channel; loss of the mitochondrial transmembrane potential; the release of cytochrome c; activation of caspases (8, 9, and 3); cleavage of poly [ADP‐ribose] polymerase‐1; production of reactive oxygen species; the depletion of glutathione (GSH); nuclear damage; and cell death in keratinocytes treated with TRAIL. These results suggest that 3,4,5‐tricaffeoylquinic acid may reduce TRAIL‐induced apoptosis in human keratinocytes by suppressing the activation of the caspase‐8 and Bid pathways and the mitochondria‐mediated cell death pathway. The effect appears to be associated with the inhibitory effect on the production of reactive oxygen species and depletion of GSH. 3,4,5‐Tricaffeoylquinic acid appears to be effective in the prevention of TRAIL‐induced apoptosis‐mediated skin diseases. Copyright © 2015 John Wiley & Sons, Ltd.     

Liquiritigenin induces mitochondria‐mediated apoptosis via cytochrome c release and caspases activation in heLa Cells

It has been demonstrated that many flavonoids possess a potent and broad spectrum of antitumor activity. Liquiritigenin is a flavanone extracted from Glycyrrhizae. This study investigated the effects of liquiritigenin on cell viability and apoptosis induction in human cervical carcinoma (HeLa) cells. The results show that liquiritigenin significantly suppressed cell proliferation in a dose‐ and time‐dependent manner in HeLa cells. In addition, liquiritigenin promoted apoptosis in HeLa cells, evidenced by apoptotic morphological changes and Annexin‐V binding. The apoptosis induction with liquiritigenin is associated with the up‐regulation of p53 and Bax, along with down‐regulation of Bcl‐2 and survivin. Finally, examination of the mitochondrial pathway of apoptosis revealed that cytochrome c is released from mitochondria to cytosol, associated with the activation of caspase‐9 and ‐3, and the cleavage of poly (ADP‐ribose) polymerase (PARP). Overall, the results indicate that liquiritigenin induces apoptosis in part via the mitochondrial pathway, which is associated with p53 up‐regulation, release of cytochrome c and elevated activity of caspase‐9 and ‐3 in HeLa cells. Copyright © 2010 John Wiley & Sons, Ltd.     

Aloe‐emodin Induces Apoptosis in Human Liver HL‐7702 Cells through Fas Death Pathway and the Mitochondrial Pathway by Generating Reactive Oxygen Species

Aloe‐emodin (1,8‐dihydroxy‐3‐hydroxymethyl‐anthraquinone) is one of the primary active compounds in total rhubarb anthraquinones isolated from some traditional medicinal plants such as Rheum palmatum L. and Cassia occidentalis, which induce hepatotoxicity in rats. Thus, the aim of this study was to determine the potential cytotoxic effects and the underlying mechanism of aloe‐emodin on human normal liver HL‐7702 cells. The CCK‐8 assays demonstrated that aloe‐emodin decreased the viability of HL‐7702 cells in a dose‐dependent and time‐dependent manner. Aloe‐emodin induced S and G2/M phase cell cycle arrest in HL‐7702 cells. This apoptosis was further investigated by flow cytometry and nuclear morphological changes by DAPI staining, respectively. Moreover, aloe‐emodin provoked the production of intracellular reactive oxygen species and the depolarization of mitochondrial membrane potential (MMP). Further studies by western blot indicated that aloe‐emodin dose‐dependently up‐regulated the levels of Fas, p53, p21, Bax/Bcl‐2 ratio, and cleaved caspase‐3, ‐8, ‐9, and subsequent cleavage of poly(ADP‐ribose)polymerase (PARP). Taken together, these results suggest that aloe‐emodin inhibits cell proliferation of HL‐7702 cells and induces cell cycle arrest and caspase‐dependent apoptosis via both Fas death pathway and the mitochondrial pathway by generating reactive oxygen species, indicating that aloe‐emodin should be taken into account in the risk assessment for human exposure. Copyright © 2017 John Wiley & Sons, Ltd.     

Antiproliferative activity and apoptosis induction by trijuganone C isolated from the root of Salvia miltiorrhiza Bunge (Danshen)

In this study, we found that the hexane fraction of Danshen, the dried root of Salvia miltiorrhiza (Lamiaceae), exerted antiproliferative effects on human leukemia cells. Phytochemical investigation of the hexane fraction achieved the isolation of the tanshinone diterpenes: dihydrotanshinone I ( 1 ), trijuganone C ( 2 ), trijuganone B ( 3 ), cryptotanshinone ( 4 ), tanshinone IIA ( 5 ), and tanshinone I ( 6 ). Compound 2 showed significant antiproliferative activities against human leukemia cells HL‐60, Jurkat, and U937. The antiproliferative activities of 2 against human cancer and normal cells indicated that 2 exhibited potent antiproliferative activities with IC₅₀ values less than 10 μM against HL‐60 and Jurkat cells as well as on the colon cancer cells DLD‐1, COLO 205, and Caco‐2. Compound 2 induced chromatin condensation, DNA fragmentation, activation of caspase‐3, ‐8, and ‐9, and the cleavage of poly (ADP‐ribose) polymerase (PARP) in HL‐60 cells. Moreover, 2 activated Bid and Bax, leading to the loss of mitochondrial membrane potential, and 2 induced the cytochrome c release from mitochondria into cytosol. In contrast, Bcl‐2 and Bcl‐xL were unaffected by 2 . These results suggest that 2 exerts antiproliferative effects via apoptosis induction mediated by mitochondrial dysfunction and caspase activation. Compound 2 may serve as a candidate of potential chemotherapeutic agent for human leukemia.     

Pachymic Acid Induces Apoptosis of EJ Bladder Cancer Cells by DR5 Up‐Regulation,ROS Generation,Modulation of Bcl‐2 and IAP Family Members

Pachymic acid (PA) is a lanostane‐type triterpenoid derived from Poria cocos mushroom that possess various biological effects such as anti‐cancer, antiinflammatory and anti‐metastasis effects. In this study, we investigated the anti‐cancer effects of PA in EJ bladder cancer cells. The results showed that PA significantly inhibited proliferation of EJ cells in a dose‐dependent manner. PA induced accumulation of sub‐G1 DNA content (apoptotic cell population), apoptotic bodies and chromatin condensation and DNA fragmentation in EJ cells in a dose‐dependent manner. PA also induces activation of caspase‐3, ‐8 and ‐9, and subsequent cleavage of poly (ADP‐ribose) polymerase, and significantly suppressed the inhibitor of apoptosis protein family proteins in a dose‐dependent manner. Furthermore, PA activates Bid and induced the loss of mitochondrial membrane potential (ΔΨ_m) with up‐regulated pro‐apoptotic proteins (Bax and Bad), down‐regulated anti‐apoptotic proteins (Bcl‐2 and Bcl‐xL) and cytochrome c release. In turn, PA increased the generation of reactive oxygen species (ROS); also, the ROS production was blocked by N‐acetyl‐L‐cysteine. The expressions of TNF‐related apoptosis inducing ligand and death receptor 5 were up‐regulated by PA in a dose‐dependent manner, suggesting extrinsic pathway also involved in PA‐induced apoptosis. This study provides evidence that PA might be useful in the treatment of human bladder cancer. Copyright © 2015 John Wiley & Sons, Ltd.     

[6]‐Shogaol,a Novel Chemopreventor in 7,12‐Dimethylbenz[a]anthracene‐induced Hamster Buccal Pouch Carcinogenesis

Oral cancer is a major cause of morbidity and mortality in developing countries. Despite advances in chemotherapy for the cancer management, the survival rate has not yet been improved. Dietary nutrient has been receiving a lot of attention and interest in the chemotherapeutic development. [6]‐Shogaol is a major bioactive compound identified in ginger that possesses many pharmacological properties. The aim of the present study is to investigate the effect of [6]‐shogaol on 7,12‐dimethylbenz[a]anthracene‐induced hamster buccal pouch (HBP) carcinogenesis. Oral squamous cell carcinoma induced in HBP by painting with 0.5% 7,12‐dimethylbenz(a)anthracene (DMBA), thrice in a week for 16 weeks. We observed 100% tumour incidence, decreased levels of lipid peroxidation, antioxidant, and phase II detoxification enzymes (GST, GR and GSH) in DMBA‐induced hamsters. Further, enhanced activity of phase I enzymes (cytochrome p450 and b5) and over‐expression of mutant p53, Bcl‐2 and decreased expression of wild type p53 and Bax were noticed in DMBA‐induced hamsters. Our results indicated that [6]‐shogaol (10, 20 and 40 mg/kg body weight) treated with DMBA‐painted hamsters, considerably reversed tumour incidence, improved antioxidant status, phase II detoxification enzymes, and also inhibit lipid peroxidation and phase I enzymes. Moreover, [6]‐shogaol inhibits mutant p53 and Bcl‐2 expression and significantly restored normal p53, Bax levels. Thus, we concluded that [6]‐shogaol prevents DMBA‐induced HBP carcinogenesis through its antioxidant as well as modulating apoptotic signals. Copyright © 2016 John Wiley & Sons, Ltd.     

Pongapin and Karanjin,furanoflavanoids of Pongamia pinnata,induce G2/M arrest and apoptosis in cervical cancer cells by differential reactive oxygen species modulation,DNA damage,and nuclear factor kappa‐light‐chain‐enhancer of activated B cell signaling

In this study, the antitumor activity of two furanoflavanoid derivatives, Pongapin and Karanjin, was evaluated in comparison with Plumbagin, a plant‐derived polyphenol with proven antitumor activity. The compounds differentially inhibit the growth of different cancer cell lines (most effective on HeLa cells), with very low inhibitory effect on the growth of normal mouse embryonic fibroblast cell line. Pongapin like Plumbagin could significantly increase the intracellular reactive oxygen species (ROS) in the HeLa cells by stabilization of nuclear factor of kappa light polypeptide gene enhancer in B‐cells inhibitor (I‐κB) expression and reduction of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) expression. In contrast, Karanjin could decrease ROS level by inhibition of I‐κB degradation resulting restriction of NF‐κB nuclear translocation. Pongapin and Plumbagin significantly increased DNA damage‐induced p53 expression and p21 nuclear expression. However, Karanjin treatment showed low DNA damage with increased p53 expression. The compounds induced G2/M arrest and increase in SubG1 population, indicating induction of apoptosis. Apoptosis was further validated by acridine orange/ethidium bromide dual staining and terminal deoxynucleotidyl transferase dUTP nick‐end labeling assay in HeLa cells after treatment with the compounds. The compounds induced caspase‐dependent apoptosis through induction of Bax/Bcl‐2 ratio either through increased expression of Bax by Pongapin and Plumbagin or low expression of Bcl‐2 by Karanjin. Thus, Pongapin and Karanjin may be potential natural anticancer agents in the future, like Plumbagin.     

Cytotoxic Impact of Costunolide Isolated from Costus speciosus on Breast Cancer via Differential Regulation of Cell Cycle—An In‐vitro and In‐silico Approach

Costunolide, a sesquiterpene lactone, is a biologically active molecule found in most of the medicinally valuable plants. The present study aims to evaluate the anticancer property of costunolide isolated from Costus speciosus against breast cancer cell lines (MCF‐7 and MDA‐MB‐231). Costunolide effectively reduced the viability of both MCF‐7 and MDA‐MB‐231 cell lines at an IC₅₀ value of 40 μM. Flow cytometric analysis revealed costunolide mediated cell cycle arrest at G2/M phase in both the cell types. Western blotting results confirmed the alterations in the expression of cell cycle regulators (cyclin D1, D3, CDK‐4, CDK‐6, p18 INK4c, p21 CIP1/Waf‐1 and p27 KIP1) and apoptosis inducers (caspase‐3 and caspase‐9) upon costunolide treatment in comparison with their expressions in normal breast cell line (MCF‐10A). Costunolide mediated downregulation of positive cell cycle regulators and upregulation of negative cell cycle regulators were related to the induction of apoptosis in cancer cells. The above results were validated with in‐silico results that predicted stable interactions between costunolide and cancer targets. Thus costunolide effectively induced breast cancer cell apoptosis targeting cell cycle regulation, and the compound can be used as an effective herbal therapeutic molecule to treat breast cancer with further explorations. Copyright © 2015 John Wiley & Sons, Ltd.     

Paris saponin VII induces cell cycle arrest and apoptosis by regulating Akt/MAPK pathway and inhibition of P‐glycoprotein in K562/ADR cells

Paris saponinVII (PSVII) is a steroidal saponin isolated from the roots and rhizomes of Trillium tschonoskii Maxim. We found that PSVII could inhibit the growth of adriamycin‐resistant human leukemia cells (K562/ADR) in a dose‐dependent manner. Furthermore, the molecular mechanism underlying the cytotoxicity and downregulation of P‐glycoprotein (P‐gp) expression by PSVII was clarified. PSVII significantly suppressed cell proliferation by cell cycle arrest in the G0/G1 phase, which was associated with an obvious decrease in cyclin B1/D1 and CDK2/4/6 protein expression. Moreover, PSVII could attenuate mitochondrial membrane potential, increase the expression of apoptosis‐related proteins, such as Bax and cytochrome c, and decrease the protein expression levels of Bcl‐2, caspase‐9, caspase‐3, PARP‐1, and p‐Akt. We also found that JNK, ERK1/2, and p38 were regulated by PSVII in K562/ADR cells. And further studies indicated that the decrease in the reactive oxygen species level inhibited intrinsic P‐gp expression. Therefore, PSVII‐induced apoptosis in K562/ADR cells was associated with Akt/MAPK and the inhibition of P‐gp. In addition, PSVII induced a robust autophagy in K562/ADR cells as demonstrated by the degradation of LC3‐I. These results provide a biochemical basis for possible clinical applications of PSVII in the treatment of leukemia.     

Herbal formula Renshenwuweizi decoction induces p53-mediated cell cycle arrest and apoptosis in A549 cells

OBJECTIVE: To investigate the effect of Renshenwuweizi decoction(RSWWZ decoction) on the growth of non-small cell lung cancer cells in vitro.METHODS: A549 non-small cell lung cancer cells were divided into two groups: control and RSWWZ decoction treatment groups. Cell Counting Kit-8 was used to measure the inhibitory effect of RSWWZ decoction on the growth of A549 cells. 4’, 6-diamidino-2-phenylindole staining and Annexin V-fluorescein isothiocyanate/propidium iodide double staining were used to...     

A p‐Menth‐1‐ene‐4,7‐diol (EC‐1) from Eucalyptus camaldulensis Dhnh. Triggers Apoptosis and Cell Cycle Changes in Ehrlich Ascites Carcinoma Cells

Anticancer activities of p‐menth‐1‐ene‐4,7‐diol (EC‐1) isolated from Eucalyptus camaldulensis Dhnh. were studied on Ehrlich ascites carcinoma (EAC) cells by MTT (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide) assay. Anticancer activities also analyzed in EAC‐bearing mice by assessment of cancer growth inhibition, changes in cancer volume, changes in life span, and hematological parameters. Apoptosis was analyzed by fluorescence microscope, DNA fragmentation assay, and flow cytometry. The expression of apoptosis‐related genes, Bcl‐2, Bcl‐X, PARP‐1, p53, and Bax, were analyzed using polymerase chain reaction (PCR). EC‐1 significantly inhibited proliferation of EAC cells in vivo and restored the altered hematological parameters of EAC‐bearing mice. Cytological observation by fluorescence microscope showed apoptosis of EAC cells upon treatment with EC‐1. Also, DNA fragmentation assay revealed EAC cells' apoptosis following EC‐1 treatment. Increased mRNA expressions of p53 and Bax genes and negative expressions of Bcl‐2 and Bcl‐X were observed in cells treated with EC‐1. These findings confirmed the induction of apoptosis by EC‐1. In addition, MTT assay showed dose‐dependent anticancer activity of EC‐1 against EAC cell. Cell cycle analysis revealed that EC‐1 treatment caused suppression of EAC cells at S phase. To conclude, EC‐1 is a novel anticancer compound and showed antiproliferative and apoptotic activities in cellular and mice models. Copyright © 2015 John Wiley & Sons, Ltd.     

Corosolic Acid Triggers Mitochondria and Caspase‐dependent Apoptotic Cell Death in Osteosarcoma MG‐63 Cells

The response of osteosarcoma MG‐63 cells to corosolic acid treatment has been investigated. The results showed that corosolic acid significantly inhibited cell viability in both a dose and a time dependent manner. It was found that corosolic acid increased the Bax/Bcl‐2 ratio by up‐regulating Bax expression, disrupted mitochondrial membrane potential and triggered the release of cytochrome c from mitochondria into the cytoplasm. Corosolic acid treatment triggered the activation of caspase‐8, 9 and 3. The apoptosis was obviously inhibited by pretreatment with a general caspase inhibitor, z‐VAD‐FMK. Moreover, pretreatment of CsA, a cyclophilin D ligand that inhibits mitochondria potential uncoupling, prevented the activation of caspase‐9 and caspase‐3, but not caspase‐8, and the apoptosis of MG‐63 cells, triggered by corosolic acid. All these results indicated that corosolic acid‐induced apoptosis was associated with the activation of caspases via a mitochondrial pathway. Copyright © 2011 John Wiley & Sons, Ltd.     

Triggering of p38 MAPK and JNK Signaling is Important for Oleanolic Acid‐Induced Apoptosis via the Mitochondrial Death Pathway in Hypertrophic Scar Fibroblasts

Hypertrophic scarring is characterized by collagen overproduction and excessive deposition of extracellular matrix. No consensus arises currently about the best therapeutics to produce complete and permanent improvement of scars with few side effects. In the present study, the mechanism of oleanolic acid (OA)‐induced apoptosis in hypertrophic scar fibroblasts (HSFs) was investigated for the first time. OA activated the protein phosphorylation of p38 MAPK and JNK but not ERK. OA did not antagonize the inhibitory effects of SB203580 on p38 MAPK pathway activity but sharply enhanced JNK phosphorylation when HSFs were pretreated with SB203580. Similarly, the inhibition of JNK signal pathway activation by pretreatment with SP600125 facilitated the protein phosphorylation of p38 MAPK caused by OA. Inhibition of p38 MAPK and/or JNK by inhibitors significantly enhanced cell viability and OA only partially depressed the increased cell viability. Moreover, OA increased Bax translocation, MMP loss, mitochondrial cytochrome c and AIF release, Bax and caspase‐3 protein expression and the ratio of Bax to Bcl‐2, decreased Bcl‐2 protein expression, and elevated the mRNA expression of Apaf‐1, caspase‐9, and capase‐3. These results suggest that OA elicits apoptosis through triggering of p38 MAPK and JNK signaling and activation of the mitochondrial death pathway. OA might be a good and useful natural drug against hypertrophic scars. Copyright © 2014 John Wiley & Sons, Ltd.     

Zerumbone Suppresses IL‐1β‐induced Cell Migration and Invasion by Inhibiting IL‐8 and MMP‐3 Expression in Human Triple‐negative Breast Cancer Cells

Inflammation is a key regulatory process in cancer development. Prolonged exposure of breast tumor cells to inflammatory cytokines leads to epithelial‐mesenchymal transition, which is the principal mechanism involved in metastasis and tumor invasion. Interleukin (IL)‐1β is a major inflammatory cytokine in a variety of tumors. To date, the regulatory mechanism of IL‐1β‐induced cell migration and invasion has not been fully elucidated. Here, we investigated the effect of zerumbone (ZER) on IL‐1β‐induced cell migration and invasion in breast cancer cells. The levels of IL‐8 and matrix metalloproteinase (MMP)‐3 mRNA were analyzed by real‐time polymerase chain reaction. The levels of secreted IL‐8 and MMP‐3 protein were analyzed by enzyme‐linked immunosorbent assay and western blot analysis, respectively. Cell invasion and migration was detected by Boyden chamber assay. The levels of IL‐8 and MMP‐3 expression were significantly increased by IL‐1β treatment in Hs578T and MDA‐MB231 cells. On the other hand, IL‐1β‐induced IL‐8 and MMP‐3 expression was decreased by ZER. Finally, IL‐1β‐induced cell migration and invasion were decreased by ZER in Hs578T and MDA‐MB231 cells. ZER suppresses IL‐1β‐induced cell migration and invasion by inhibiting IL‐8 expression and MMP‐3 expression in TNBC cells. ZER could be a promising therapeutic drug for treatment of triple‐negative breast cancer patients. Copyright © 2014 John Wiley & Sons, Ltd.